Neuroprotective polyphenol analogs

Abstract

The present invention provides neuroprotective polyphenol compounds, which can be synthetic analogs of fisetin, baicalein or chlorogenic acid, that maintain neuroprotective, anti-inflammatory, glutathione promoting, and/or antioxidant properties. The neuroprotective polyphenol compounds are useful for promoting, enhancing and/or increasing neuron protection, growth and/or regeneration. The polyphenol compounds further find use for increasing and or maintaining intracellular glutathione (GSH) levels. The polyphenol compounds are also useful for treating, preventing, mitigating and/or delaying neurodegenerative conditions, including diabetes, Parkinson's disease, Huntington's disease, Alzheimer's disease, non-Alzheimer's dementias, multiple sclerosis, traumatic brain injury, spinal cord injury or ALS.

The invention claimed is: 
     
       1. A compound having a formula I 
       
         
           
           
               
               
           
         
         or a structure selected from 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Z is N and 
       
       
         
           
           
               
               
           
         
         R 1  is —N(R c ) 2 ; 
         R 2  is H, optionally substituted C 1-6 alkyl, —OR a , —NO 2  or —N(R c ) 2 ; 
         R 3  is H, optionally substituted C 1-6 alkyl or —OR a ; 
         R 4  is C 1-6 alkyl; 
         each R 5  is, independently for each occurrence, R e , R b , R e  substituted with one or more of the same or different R a  and/or R b , —OR e  substituted with one or more of the same or different R a  and/or R b , —SR e  substituted with one or more of the same or different R a  and/or R b , —C(O)R e  substituted with one or more of the same or different R a  and/or R b , —N(R a )R e  where R e  is substituted with one or more of the same or different R a  and/or R b , —(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —R b , —S—(C(R a ) 2 ) m —R b , —O—(C(R b ) 2 ) m —R a , —N(R a )—(C(R a ) 2 ) m —R b , —O—(CH 2 ) m —CH((CH 2 ) m R b )R b , —C(O)N(R a )—(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2  ) m —R b , —N((C(R a ) 2 ) m R b ) 2 , —S—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2 ) m —R b , —N(R a )—C(O)—N(R a )—(C(R a ) 2 ) m —R b , —N(R a )—C(O)—(C(R a ) 2 ) m —C(R a )(R b ) 2  or —N(R a )—(C(R a ) 2 ) m —C(O)—N(R a )—(C(R a ) 2 ) m —R b , or , alternatively, two of R 5 , together with the vicinal carbons to which they are attached, combine to form a 4-10 membered unsaturated, or partially saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R a  and/or R b ; 
         each R 6  is, independently for each occurrence, R e , R b , R e  substituted with one or more of the same or different R a  and/or R b , —OR e  substituted with one or more of the same or different R a  and/or R b , —SR e  substituted with one or more of the same or different R a  and/or R b , —C(O)R e  substituted with one or more of the same or different R a  and/or R b , —N(R a )R e  where R e  is substituted with one or more of the same or different R a  and/or R b , —(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —R b , —S—(C(R a ) 2 ) m —R b , —O—(C(R b ) 2 ) m —R a , —N(R a )—(C(R a ) 2 ) m —R b , —O—(CH 2 ) m —CH((CH 2 ) m R b )R b , —C(O)N(R a )—(C(R a ) 2 ) m —R b , —O—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2 ) m —R b , —N((C(R a ) 2 ) m R b ) 2 , —S—(C(R a ) 2 ) m —C(O)N(R a )—(C(R a ) 2 ) m —R b , —N(R a )—C(O)—N(R a )—(C(R a ) 2 ) m —R b , —N(R a )—C(O)—(C(R a ) 2 ) m —C(R a )(R b ) 2  or —N(R a )—(C(R a ) 2 ) m —C(O)—N(R a )—(C(R a ) 2 ) m —R b , or , alternatively, two of R 6 , together with the vicinal carbons to which they are attached, combine to form a 4-10 membered unsaturated, or partially saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R a  and/or R b ; 
         each R a  is independently for each occurrence H, C 1-6 alkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl; 
         each R b  is independently for each occurrence ═O, ═S, —OR a , —O—(C(R a ) 2 ) m —OR a , —SR a , ═NR a , ═NOR a , —N(R c ) 2 , halo , —CF 3 , —CN, —NO 2 , —S(O)R a , —S(O) 2 R a , —SO 3 R a , —S(O) 2 N(R c ) 2 , —C(O)R a , —CO 2 R a , —C(O)N(R c ) 2 , —OC(O)N(R c ) 2 , —[N(R a )C(O)] n R a , —[N(R a )C(O)] n OR a  or —[N(R a )C(O)] n N(R c ) 2 ; 
         each R c  is independently for each occurrence R a , or, alternatively, two R C  are taken together with the nitrogen atom to which they are bonded to form a 3 to 10-membered heteroalicyclyl or a 5-10 membered heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which is optionally substituted with one or more of the same or different R a  and/or R d  groups; 
         each R d  is ═O, —OR a , haloC 1-3 alkyloxy, C 1-6 alkyl, ═S, —SR a , —N(R a ) 2 , halo , —CF 3 , —CN, —NO 2 , —S(O)R a , —S(O 2 )R a , —SO 3 R a , —S(O) 2 N(R a ) 2 , —C(O)R a , —CO 2 R a , —C(O)N(R a ) 2 , —OC(O)N(R a ) 2 , —[N(R a )C(O)] n R a , —(C(R a ) 2 ) n —OR a , —C(O)—C 1-6 haloalkyl, —OC(O)R a , —O(C(R a ) 2 ) m —OR a , —S(C(R a ) 2 ) m —OR a , —N(R a )—(C(R a ) 2 ) m —OR a , —[N(R a )C(O)] n OR a , —[N(R a )C(O)] n N(R a ) 2  or —N(R a )C(O)C 1-6 haloalkyl, or, alternatively, two R d , taken together with the atom or atoms to which they are attached, combine to form a 3-10 membered partially or fully saturated mono or bicyclic ring, optionally containing one or more heteroatoms and optionally substituted with one or more R a ; 
         each R e  is independently for each occurrence C 1-6 alkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl; 
         each m is 1, 2 or 3; 
         each n is 0, 1, 2 or 3; 
         x is 0, 1, 2, 3 or 4; and 
         y is 0, 1, 2 or 3. 
       
     
     
       2. The compound of  claim 1 , according to Formula IIA 
       
         
           
           
               
               
           
         
         wherein: 
         each R 5  is, independently for each occurrence, C 1-6 alkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, —OR a , —O—(C(R a ) 2 ) m —OR a , —SR a , —N(R c ) 2 , halo, —CF 3 , —CO 2 R a , —C(O)N(R c ) 2 , or two of R 5 , together with the vicinal carbons to which they are attached, combine to form a 6-membered unsaturated aryl ring, the 6-membered aryl ring optionally substituted with one or more R a  and/or R b ; and 
         each R 6  is, independently for each occurrence, C 1-6 alkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, —OR a , —O—(C(R a ) 2 ) m —OR a , —SR a , —N(R c ) 2 , halo, —CF 3 , —CO 2 R a , —C(O)N(R c ) 2 . 
       
     
     
       3. The compound of  claim 2 , wherein:
 (a) the compound is of Formula IIA; R 2  is —OR a ; and R 3  is H or optionally substituted C 1-6 alkyl; or 
 (b) the compound is of Formula IIA; R 2  is H; and R 3  is H or optionally substituted C 1-6 alkyl. 
 
     
     
       4. The compound of  claim 1 , wherein R 2  is H or OH. 
     
     
       5. The compound of  claim 2 , wherein the compound is of Formula IIA, R 2  is —OR a , and R 3  is H. 
     
     
       6. The compound of  claim 5 , wherein R 2  is —OH. 
     
     
       7. The compound according to  claim 1 , wherein the compound is:
 4-ethoxy-2-(3,4-dihydroxyphenyl)quinoline (CMS-023); 
 4-cyclopentyloxy-2-(3,4-dihydroxyphenyl)quinoline (CMS-121); 
 4-methoxy-2-(4-dimethylaminophenyl)quinoline (CMS-109); 
 4-methoxy-2-(4-(pyrrolidin-1-yl)phenyl)quinoline (CMS-110); 
 4-isopropoxy-2-(4-dimethylaminophenyl)quinoline (CMS-112); or 
 4-isopropoxy-2-(4-(pyrrolidin-1-yl)phenyl)quinoline (CMS-113). 
 
     
     
       8. The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
       9. A pharmaceutical composition comprising one or more compounds of  claim 1 , and a pharmaceutically acceptable carrier, excipient or vehicle. 
     
     
       10. A method of promoting, increasing, and/or enhancing the protection, growth and/or regeneration of neurons, comprising administering an effective amount of one or more compounds of  claim 1  to the neurons. 
     
     
       11. The method of  claim 10  wherein the method promotes, increases, and/or enhances the protection, growth and/or regeneration of neurons by maintaining glutathione levels. 
     
     
       12. The compound of  claim 1 , wherein R 4  is C 3-6 cycloalkyl. 
     
     
       13. The compound of  claim 1 , wherein R 5  is C 3-6 cycloalkyl. 
     
     
       14. The compound of  claim 1 , wherein R 6  is C 3-6 cycloalkyl. 
     
     
       15. The compound of  claim 1 , wherein each Ra is independently for each occurrence H, C 3-6 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl. 
     
     
       16. The compound of  claim 1 , wherein each Re is independently for each occurrence C 3-6 cycloalkyl, C 4-11 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 3-10 membered heteroalicyclyl, 4-11 membered heteroalicyclylalkyl, 5-15 membered heteroaryl or 6-16 membered heteroarylalkyl.